1. Field of Invention.
The present invention relates to certain novel N-(3-quinuclidinyl)benzamides and thiobenzamides; namely, the 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides and thiobenzamides which exhibit gastrokinetic and anti-emetic properties in warm blooded animals with minimal neuropharmacological side effects. The invention is also concerned with methods of and compositions for increasing gastric emptying and alleviating emesis, particularly emesis due to administration of platinum anticancer drugs such as cisplatin.
2. Information Disclosure Statement.
Quinuclidine analogs of sulpiride were prepared and studied by Mikhlina, E. E. et al as reported in Khim-Farmatsevt, Zh. 10. No. 11, 56-60 (1976); C.A. 86 : 155489r exemplified by the compound: 5-aminosulfonyl-N-[1-azabicyclo [2.2.2]oct-3-yl)-2-methoxybenzamide. This compound and others in the series were reported by the authors not to have antiemetic activity. The above named compound was reported in USSR Pat. No. SU-414-261 to have neuroleptic activity. In comparison, the compounds of the present invention show strong gastrokinetic and antiemetic activity without neuroleptic activity {blockade of d-amphetamine lethality in mice).
Syntheses of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl) benzamide and N-[1-azabicyclo[2.2.2]oct-3-yl)benzamide were reported by Mikhlina, E. E. et al in Khim-Farmatsevt. Zh. 7, 20-24 (1974); C.A. 79, 146358a and the latter in Khim. Geterosikl. Soedin., Akad. Nauk. Latv. SSR 243-9 (1966); C.A. 65: 2220b. These compounds were reported to exhibit hypotensive, narcotic and ganglionic stimulation and blocking activities, properties not seen in the compounds of the present invention.
Synthesis of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-3-chloro-5-trifluoromethylbenzamid e was reported in Ger. Offen. No. 2,548,968; C.A. 87, 68001c and in equivalently related U.S. Pat. No. 4,093,734 from 4-amino-3-chloro-5-trifluoromethyl benzoic acid chloride and 3-aminoquinuclidine. The compound is in a class among pyrrolidinyl and piperidinyl benzamides which are said to be useful as anxiolytics, anticonvulsives, antiemetics and antiulcerogenics. None of the compounds have orthoalkoxy substitution on benzamide as do the compounds of the present invention.
It is widely recognized that substituted benzamides are a class of drugs known to be effective in psychiatry and gastroenterology (Sulpiride and other Benzamides; International Workshop on Sulpiride and other benzamides, Florence, Feb. 17-18 (1978), Raven Press]. However, the 2-alkoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamides of this invention exhibit effects only on gastrointestinal motility and do not show neuropharmacological activity. This is in marked contrast to the compounds described in the prior art which show a range of pharmacological activities that include both neuropharmacological and gastrointestinal effects.